Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability

  • EMBO Mol Med. 2016 Apr 1;8(4):363-74. doi: 10.15252/emmm.201506106.
Andrew Dauber  1 ,  María T Muñoz-Calvo  2 ,  Vicente Barrios  2 ,  Horacio M Domené  3 ,  Soren Kloverpris  4 ,  Clara Serra-Juhé  5 ,  Vardhini Desikan  6 ,  Jesús Pozo  2 ,  Radhika Muzumdar  7 ,  Gabriel Á Martos-Moreno  2 ,  Federico Hawkins  8 ,  Héctor G Jasper  3 ,  Cheryl A Conover  9 ,  Jan Frystyk  10 ,  Shoshana Yakar  11 ,  Vivian Hwa  1 ,  Julie A Chowen  2 ,  Claus Oxvig  4 ,  Ron G Rosenfeld  12 ,  Luis A Pérez-Jurado  5 ,  Jesús Argente  13
Affiliations
  • 1. Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 2. Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid, Madrid, Spain Program of Pediatric Obesity, CIBEROBN Instituto de Salud Carlos III, Madrid, Spain.
  • 3. Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
  • 4. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • 5. Genetics Unit, Universitat Pompeu Fabra Hospital del Mar Research Institute (IMIM) & CIBERER. Instituto de Salud Carlos III, Barcelona, Spain.
  • 6. Department of Pediatrics, Division of Pediatric Endocrinology, New York Medical College, Valhalla NY, USA.
  • 7. Division of Endocrinology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 8. Department of Endocrinology, Hospital Universitario 12 de Octubre Universidad Complutense de Madrid, Madrid, Spain.
  • 9. Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
  • 10. Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • 11. Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
  • 12. Oregon Health and Science University, Portland, OR, USA STAT5 LLC, Los Altos, CA, USA.
  • 13. Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid, Madrid, Spain Program of Pediatric Obesity, CIBEROBN Instituto de Salud Carlos III, Madrid, Spain [email protected].
PMID: 26902202 DOI: 10.15252/emmm.201506106
Abstract

Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs.

Keywords
IGF bioavailability; IGF‐binding proteins; bone; delayed growth; growth hormone.